Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 3-month-old male infant presented with pallor, hepatomegaly (4.5 cm), splenomegaly (1.5 cm), anaemia (Hb 6 g/dl) and thrombocytopenia (16 X 10(9)/l). A liver biopsy was diagnostic for Langerhans cell histiocytosis (histiocytosis X). The patient's lymphocytes, co-cultured with neonatal lymphocytes, were positive for virus-like particles without reverse transcriptase activity. The hepatomegaly diminished after 6 months and a second liver biopsy showed decreased histiocytic infiltration. A second viral blood culture remained negative. After 14 months, the hepatomegaly had disappeared completely and there were no more abnormal haematological or clinical findings.
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PMID:Spontaneous healing of Langerhans cell histiocytosis (histiocytosis X). 326 42

The retroviruses human T-cell lymphotrophic virus-I (HTLV-I) and HTLV-III/LAV (lymphadenopathy-associated virus) are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV). Because HTLV-III infects only humans and chimpanzees, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT) is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.
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PMID:Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine. 346 67

Interleukin 12 (IL-12) activates natural killer (NK) and T cells with the secondary synthesis and release of interferon-gamma (IFN-gamma) and other cytokines. IL-12-induced organ alterations are reported for mice and the pathogenetic role of IFN-gamma is investigated by the use of mice deficient in the IFN-gamma receptor (IFN-gamma R-/-). IL-12 caused a rapid infiltration of liver and splenic red pulp with activated macrophages; this and increased NK cells resulted in a fivefold increase of splenic weight in wild-type mice. Splenomegaly was associated with myelosuppression and decreasing peripheral leukocyte counts. IL-12-induced changes in wild-type mice were associated with markedly increased IFN-gamma serum levels and up-regulation of major histocompatibility complex (MHC) class I and II expression in various epithelia. IL-12 induced a qualitatively similar macrophage infiltration in IFN-gamma R-/- mice, less marked splenomegaly (to 2 x normal), and no MHC upregulation. Strikingly increased vascular endothelial intercellular adhesion molecule-1 expression was apparent in both IFN-gamma R-/- and IFN-gamma R+/+ mice. Restricted to mutant mice was a severe, invariably lethal, interstitial, and perivascular pulmonary macrophage infiltration with diffuse pulmonary edema. Extensive quantitative reverse transcriptase polymerase chain reaction analysis revealed an increase of only IL-6 and IL-10 pulmonary gene transcripts in IFN-gamma R-/- mice compared with wild-type mice. IL-12-induced myelosuppression is due to IFN-gamma-release from NK cells and T cells, and is associated with macrophage activation and distinct MHC class I and II antigen upregulation. The pulmonary pathology in IFN-gamma R-/- mice, however, reveals a toxic potential for IL-12 and suggests that endogenous IFN-gamma plays a protective role in preventing fatal pulmonary disease in these mice.
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PMID:Role of interferon-gamma in interleukin 12-induced pathology in mice. 749 76

Friend virus (FV) is a murine leukemia virus that infects progenitor red blood cells and causes an erythroleukemia in susceptible mouse strains, resulting in splenomegaly. Several genetic loci of the host have been identified that affect erythroleukemia development, differentiation status of target cells and virus replication. Since age may change expression of these loci, age may affect FV disease. To explore this possibility, FV expression in four genetically diverse strains of mice of different ages was examined. Extent of viral replication and of disease were evaluated by measuring spleen focus forming units (SFFU), spleen weight and reverse transcriptase (RT) activity in target organs. Young DBA/2 and (C57BL/6 x DBA/2)F1 mice exhibited a greater level of virus expression than their aged counterparts in all parameters investigated. Young CBA/Ca mice had slightly higher spleen weights and SFFU values than aged CBA/Ca mice, but a definitive age-related change was not observed in the RT activity of the target organs. C57BL/6 mice, which are genetically resistant to the development of FV-induced erythroleukemia, exhibited a limited degree of virus replication that was not effected by the age of the animal. Our results indicate that the age of the mouse, as well as the genetic background, can contribute to the level of susceptibility to FV.
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PMID:Differences between young and aged mice in susceptibility to Friend virus. 751 1

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (i.p.) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-beta-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the i.p. or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.
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PMID:Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice. 873 97

Rauscher murine leukemia virus induces an erythroleukemia in susceptible strains of mice that is associated with splenomegaly and viremia. This animal model has been used for evaluating the in vivo efficacy of potential anti-HIV agents. The in vivo antiviral activity of therapeutic agents has usually been determined by measuring a reduction in the spleen weights of compound-treated mice or by quantitating viremia with the UV-XC plaque assay. The UV-XC assay, however, is time-consuming and labor-intensive. Virions of Rauscher murine leukemia virus, like other retroviruses, contain the enzyme reverse transcriptase. Quantitating the level of this enzyme in infected mouse sera provides a more rapid measure of viremia in the animal. We have examined the effects of several reagents, including detergent, KCl, EGTA, dGMP, spermine, as well as protease and RNase inhibitors, on the reverse transcriptase assay. The optimized assay method was effective in evaluating the antiviral activity of AZT in the Rauscher murine leukemia virus in vivo model. The assay is also amenable to automation if large numbers of assays are required.
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PMID:Optimization of the reverse transcriptase assay for the detection of viral burden in mice infected with Rauscher murine leukemia virus. 891 Jun 49

Anti-HIV-1 combination therapies, including protease and reverse transcriptase inhibitors, can reduce plasma viremia to undetectable levels within the first 2 weeks of treatment. This reduction is followed by a slower decline that primarily results from the presence of viral reservoirs such as CD4+ memory cells, dendritic cells, and macrophages. For this reason, we evaluated a new drug combination therapy that includes a lympholytic drug: (2-fluoro-ara-AMP, fludarabine) to eliminate cells already infected and an antiviral drug (azidothymidine [AZT]) to protect cells not yet infected. We used C57BL/6 mice infected with the retroviral complex LP-BM5, which developed severe immunodeficiency (i.e., murine AIDS), to select the most effective fludarabine regimen to inhibit disease progression, and then to evaluate the efficacy and toxicity of the fludarabine and AZT combinations. The results obtained show that intraperitoneal administration of fludarabine at 3 mg/mouse twice a day for 4 weeks is the most effective regimen in reducing splenomegaly, lymphadenopathy, hypergammaglobulinemia, and proviral DNA content in spleen and lymph nodes and in restoring the architecture of lymph nodes. Subsequently, we evaluated the combined or sequential administration of fludarabine and AZT. The data reported in this paper show that the sequential administration of the two drugs provides additive antiviral effects that reduce spleen and lymph node weights to normal values and proviral DNA content by approximately 95% in all infected organs; the phenotypes of blood T and B cells moved toward control values, although the number of B cells was significantly reduced by fludarabine treatment. Finally, we evaluated the outcome of the disease after suspension or continuation of different treatment regimens. In all treatment groups, the disease progressed and increased proviral DNA content was found in infected organs, but animals receiving the sequential administration of fludarabine and AZT were less affected than those receiving only fludarabine or the simultaneous administration of both. The results obtained suggest that fludarabine could be part of a new therapeutic approach aiming at eradicating HIV from those cells that have been already infected and that are not protected by highly active antiretroviral therapy (HAART).
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PMID:Inhibition of murine AIDS by alternate administration of azidothymidine and fludarabine monophosphate. 1083 56

A 37-year-old Malay man presented initially with the clinical picture of essential thrombocythaemia (ET) without the extreme leukocytosis, marked splenomegaly and low neutrophil alkaline phosphatase characteristic of chronic myelogenous leukaemia (CML). Bone marrow examination showed massive megakaryocytic hyperplasia; cytogenetic studies showed the presence of Philadelphia chromosome. The patient was treated with hydroxyurea that resulted in reduction in the platelet count. Seventeen months later, he presented with fever associated with tender massive splenomegaly. Bone marrow finding was consistent with chronic phase CML. The presence of a rearrangement involving the major breakpoint cluster region (M-bcr) on chromosome 22 was confirmed by reverse transcriptase-polymerase chain reaction. The clinical importance of finding the Philadelphia chromosome in patients who seem to have ET is in assessing prognosis. ET generally follows a chronic, indolent course. However, this patient who had Philadelphia chromosome underwent clinical transition to chronic phase CML17 months and blast crisis 29 months after presentation.
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PMID:BCR-ABL positive essential thrombocythaemia: a variant of chronic myelogerous leukaemia or a distinct clinical entity: a special case report. 1129 85

Chronic myelogenous leukemia (CML) with a minor bcr-abl transcript is a rare entity. We describe a 66-year-old female who was diagnosed with CML in the chronic phase. Molecular analysis of her Philadelphia chromosome using the reverse transcriptase polymerase chain reaction and subsequent sequencing revealed a minor bcr-abl transcript. Monocytosis resembling chronic myelomonocytic leukemia was observed without splenomegaly and basophilia. Her clinical course was indolent and maintained the chronic phase of CML for nearly 3 years under hydroxyurea treatment. A review of the 23 cases of m-bcr CML including this case showed the presence of monocytosis and the absence of basophilia and splenomegaly in 55.0%, 55.0%, and 70.0% of patients, respectively. The absence of basophilia was a significant finding in patients without monocytosis ( P=0.01). Although the hematological features or clinical outcomes were variable in m-bcr CML cases, all three cases at the onset of the blastic phase showed lymphoid crisis, implying an increased lymphoid leukemogenicity of minor bcr-abl transcripts.
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PMID:Lymphoid preponderance and the absence of basophilia and splenomegaly are frequent in m-bcr-positive chronic myelogenous leukemia. 1197 25

There are two major forms of the BCR/ABL fusion gene, involving ABL exon 2, but including different exons of BCR gene. The transcripts b2a2 or b3a2 code for a p210 protein. Another fusion gene leads to the expression of an e1a2 transcript, which codes for a p190 protein. Another, less common fusion gene is c3a2[e19a2], which encodes a p230 protein. The incidence of one or the other rearrangement in chronic myeloid leukaemia (CML) patients varies in different reported series. This study was designed to determine the frequency of coexpresion of the p210, p190 and p230 transcripts in 250 Mexican patients with CML. We performed nested and multiplex reverse transcriptase polymerase chain reaction (RT-PCR) on bone marrow samples from adult patients and found that all cases were positive for some type of BCR/ABL rearrangement. In 226 (90.4%) patients it was p210, while the remaining 9.6% showed coexpression or one of the transcripts of p190/p210/p230. In 7% of patients with p210 expression there are both isoforms (b3a2/b2a2), presumably the result of alternative splicing. The rate of coexpression of the p190/p210 transcripts was 5%, which is much lower than in other reports. This may be due to the technical factors. These patients had high platelet counts, marked splenomegaly and chromosomal abnormalities in addition to Ph'. Other types of coexpression seen were p210/p230 and p190/p210/p230, in patients with high-risk clinical factors. Our study confirms the occurrence of coexpression of different BCR/ABL transcripts, although the rate (9.6%) was much lower than has been reported in other populations. This may reflect either the sensitivity of the detection techniques used or the possibility of genetic differences between the populations studied. Coexpression may be due to alternative splicing or to phenotypic variation, with clinical courses different from classical CML.
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PMID:BCR/ABL p210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML). 1206 77


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